Effects of angiotensin-converting enzyme inhibition on exercise-induced angina and ST segment depression in patients with microvascular angina.

OBJECTIVES: This study was conducted to test the hypothesis that angiotensin-converting enzyme inhibition may lessen myocardial ischemia in patients with microvascular angina. BACKGROUND: Patients with syndrome X (angina pectoris, positive findings on exercise testing and normal coronary arteriogram) have a reduced coronary vasodilator reserve ("microvascular angina") and may show an increased sympathetic drive. Angiotensin-converting enzyme inhibition attenuates sympathetic coronary vasoconstriction in patients with coronary artery disease. METHODS: Ten patients (seven women and three men, mean age [+/- SD] 53 +/- 6 years) with syndrome X and a reduced coronary flow reserve underwent a randomized, single-blind, crossover, placebo-controlled study of the effects of the angiotensin-converting enzyme inhibitor enalapril on angina and exercise-induced ST segment depression. Assessment was by symptom-limited treadmill exercise testing after 2 weeks of treatment with 10 mg/day of enalapril and after 2 weeks of placebo administration. RESULTS: All patients had positive findings on exercise testing (> or = 1 mm ST segment depression and angina) while taking placebo, whereas six patients had a positive test result (four with angina) during enalapril therapy. Total exercise duration and time to 1 mm of ST segment depression were prolonged by enalapril over those obtained with placebo (mean 779 +/- 141 vs. 690 +/- 148 s, p = 0.006 and 690 +/- 204 vs. 485 +/- 241 s, p = 0.007, respectively). The magnitude of ST segment depression was also less with enalapril than with placebo (mean 1.1 +/- 0.4 vs. 1.5 +/- 0.2 mm, p = 0.004). Heart rate and blood pressure at peak exercise and at 1 mm of ST depression were not significantly different during placebo and enalapril treatment. CONCLUSIONS: Angiotensin-converting enzyme inhibition lessens exercise-induced ischemia in patients with syndrome X and microvascular angina, probably by a direct modulation of coronary microvascular tone, which results in an increased myocardial oxygen supply.

Reactivity of eccentric and concentric coronary stenoses in patients with chronic stable angina.

Dynamic coronary stenoses may be the cause of a variable angina threshold and rest angina in patients with chronic stable angina. It has been suggested that eccentric but not concentric coronary artery stenoses have the potential for dynamic changes of caliber in response to vasoactive stimuli. The vasomotor response of eccentric (asymmetric narrowing) and concentric (symmetric narrowing) coronary stenoses to ergonovine (20 micrograms intracoronary or 300 micrograms intravenous) and isosorbide dinitrate (1 mg intracoronary) was studied in 51 patients with chronic stable angina. Diameter of reference segments (angiographically normal segments proximal to the stenoses) and that of eccentric (n = 30) and concentric (n = 35) coronary stenoses that ranged from 50% to 90% luminal diameter reduction were measured by computerized quantitative angiography before and after ergonovine and isosorbide dinitrate. Ergonovine reduced stenosis diameter (by greater than or equal to 10%) in 80% of eccentric stenoses and 42% of concentric stenoses (p less than 0.05). Mean (+/- SEM) diameter reduction with ergonovine was 19 +/- 3% and 9.5 +/- 2% for eccentric and concentric stenoses, respectively (p less than 0.05). Isosorbide dinitrate increased coronary diameter (by greater than or equal to 10%) in 70% of eccentric and 43% of concentric stenoses (p less than 0.05). Mean diameter of eccentric stenoses increased from 1.15 +/- 0.05 to 1.35 +/- 0.06 mm after nitrate (18.6 +/- 2.5%), whereas diameter of concentric stenoses increased from 1.05 +/- 0.05 to 1.14 +/- 0.05 mm (10 +/- 2.5%) (p less than 0.05). Average dilation of reference segments with administration of isosorbide dinitrate and constriction with ergonovine were not significantly different in patients with concentric and eccentric stenoses.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of epicardial coronary artery tone and reactivity in Prinzmetal's variant angina and chronic stable angina pectoris.

It has been suggested that a generalized coronary vasomotion disorder is present in variant angina and that evaluation of baseline coronary artery tone may be useful for predicting the occurrence of coronary artery spasm. The vasomotor response of angiographically normal proximal and distal coronary artery segments was studied in 9 patients with atypical chest pain and normal coronary arteriograms (control group), 13 patients with active variant angina and 41 patients with chronic stable angina. Ergonovine (intravenous, 100 to 300 micrograms, or intracoronary, 8 to 20 micrograms, was administered to all 22 patients in the control and variant angina groups and to 11 of the 41 patients with chronic stable angina. All patients also received intracoronary isosorbide dinitrate (1 to 2 mg). Computerized coronary artery diameter measurement of angiographically normal segments was carried out before and after ergonovine and nitrate administration. Mean baseline intraluminal diameter of proximal and distal coronary segments was not significantly different in control patients and those with variant angina (nonspastic segments only) or coronary artery disease (proximal 2.89 +/- 0.15, 2.83 +/- 0.14 and 2.82 +/- 0.09 mm; distal 1.60 +/- 0.08, 1.63 +/- 0.07 and 1.62 +/- 0.06 mm, respectively). After ergonovine, proximal segments constricted by 10 +/- 2%, 15 +/- 3% and 11 +/- 4% and distal segments by 11 +/- 3%, 11 +/- 2% and 14 +/- 3% in control, variant angina and coronary artery disease groups, respectively (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Reactivity of proximal and distal angiographically normal and stenotic coronary segments in chronic stable angina pectoris.

To assess whether vasoreactivity of significant coronary stenosis (greater than 50% intraluminal diameter reduction) and that of angiographically normal coronary segments differs in proximal and distal locations, 53 patients (40 men, 13 women, mean +/- standard deviation age 55 +/- 11 years) with chronic stable angina and angiographically documented coronary artery disease were studied. While abstaining from antianginal therapy, all 53 patients underwent coronary arteriography before and after 1 mg of intracoronary isosorbide dinitrate and 21 of the 53 also before and after 20 to 30 micrograms intracoronary ergonovine. Computerized quantitative angiography was used to assess changes in the intraluminal diameter of 126 normal coronary segments (63 proximal, 63 distal) and 43 significant coronary stenoses. Nitrates dilated proximal normal coronary segments by 7.4 +/- 1.2% and distal normal coronary segments by 15 +/- 1.7% (p less than 0.01). Significant proximal coronary stenoses dilated by 11 +/- 2.5% and distal stenoses by 23 +/- 2.8% (p less than 0.01) after nitrates. Ergonovine reduced the diameter of proximal normal coronary segments by 9.3 +/- 1.7% and that of normal distal segments by 15.5 +/- 1.4% (p less than 0.01). Proximal stenoses constricted by 11 +/- 2.2% and distal stenoses by 18.4 +/- 2.8% (p = 0.06). Analysis of segments showed that nitrates dilated 19 of 63 (30%) proximal normal segments by (greater than or equal to 10%), 31 of 63 (49%) distal (p less than 0.05) and 21 of 43 (49%) stenoses.(ABSTRACT TRUNCATED AT 250 WORDS)

Similar time course of ST depression during and after exercise in patients with coronary artery disease and syndrome X.

To assess whether the time course of ST segment depression differs in patients with coronary artery disease and patients with angina and normal coronary arteries, the exercise tests of 54 patients with documented coronary artery disease and 25 patients with syndrome X (angina, positive exercise test, no evidence of coronary artery spasm, and normal coronary arteries) were compared. All tests were performed with therapy withheld, using the modified Bruce protocol. In each test, time, heart rate and blood pressure were measured at the onset and at 1 mm of ST segment depression, and at peak exercise. Recovery (return of the ST segment to baseline +/- 0.2 mm) time was also assessed. Peak ST segment depression was similar in coronary artery disease and syndrome X patients (1.5 +/- 0.3 versus 1.6 +/- 0.4 mm). In 42 coronary artery disease patients, ST segment depression developed early (less than or equal to 6 minutes) during exercise; this was associated with a short recovery (less than or equal to 3 minutes) in 17 (40%) and with a long recovery (greater than 3 minutes) in 25 (60%) patients. In 17 patients with syndrome X, ST segment depression developed early; it was associated with a short recovery in six (35%) and with a long recovery in 11 (65%) patients. Late (greater than 6 minutes) onset of ST segment depression was observed in 12 coronary artery disease patients; of these, eight (67%) had a short recovery and 4 (33%) had a long recovery. Late onset of ST segment depression occurred in eight patients with syndrome X; six (75%) had a short recovery and two (25%) had a long recovery.(ABSTRACT TRUNCATED AT 250 WORDS)

Duration of ST segment depression after exercise-induced myocardial ischemia is influenced by body position during recovery but not by type of exercise.

To assess whether the duration of ischemic ST segment depression after exercise can be modified by changes in body position during recovery or with different types of exercise, 18 patients with chronic stable angina, positive exercise test results, and documented coronary artery disease were prospectively studied. Every patient underwent testing with three different exercise protocols: (1) Bruce (Bruce-standing recovery), (2) abrupt onset of exercise (abrupt), and (3) modified Bruce protocol preceded by a 10-minute warm-up period (warm-up). After exercise test patients recovered in a sitting position. In addition, all patients performed a fourth exercise (Bruce protocol), but this time they recovered in the supine position (Bruce-supine recovery). Time and heart rate-blood pressure product at 1 mm ST segment depression were similar for Bruce-standing recovery, abrupt, and Bruce-supine recovery protocols (5.1 +/- 2, 4.4 +/- 2, and 5.2 +/- 2 minutes and 20.8 +/- 4, 21.3 +/- 4, and 20.4 +/- 4 beats/min x mm Hg x 10(-3), respectively. Heart rate and heart rate-blood pressure product at peak exercise did not differ in Bruce-standing recovery, abrupt, and Bruce-supine recovery. Maximal ST segment depression was -2.0, -1.9, and -2.0 mm with Bruce-standing recovery, abrupt, and Bruce-supine recovery exercise, respectively, and -1.5 mm with warm-up exercise (p less than 0.05). Duration of ST segment depression into recovery was significantly prolonged after Bruce-supine recovery exercise (9.4 + 5 minutes) compared with Bruce-standing recovery, abrupt, and warm-up protocols (6.8 + 3, 5.9 + 4, and 5.0 + 3 minutes, respectively; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Duration and magnitude of ST-segment depression during exercise and recovery: a symmetric relation.

The pattern of appearance and disappearance of ST depression on 12-lead electrocardiographic exercise testing in subjects with coronary artery disease (> or = 70% stenosis) and its relation to the severity of disease were prospectively explored in 34 consecutive patients. The first lead to show positivity during exercise also developed maximum ST depression in 73% of patients and was the last lead to lose positivity in recovery (94%). The last lead to show positivity during exercise was first to lose positivity in recovery (92%). Greater ST depression was associated with a greater number of positive leads (p < 0.001; r = 0.7). The duration of ST depression during exercise, maximum ST depression, and recovery time were related (p = 0.001, r = 0.6; p = 0.006, r = 0.5; p < 0.001, r = 0.6, respectively, for the three interactions). However, the correlations of ST depression and recovery time with the severity of vessel disease and with rate-pressure product at initial ST depression were poor, suggesting that the degree of ST-segment depression and recovery time may depend more on the duration and intensity of myocardial ischemia solicited with exercise rather than on the ischemic threshold or on the severity of coronary artery disease.

Heart rate response during exercise testing and ambulatory ECG monitoring in patients with syndrome X.

The response of the heart rate during exercise testing and 24-hour ambulatory electrocardiographic (ECG) monitoring performed with patients not receiving antianginal treatment was assessed in 26 patients (9 men and 17 women; mean age 51 +/- 8 years) with syndrome X (angina pectoris with normal coronary arteries), in 27 patients with coronary artery disease (10 men and 17 women; mean age 55 +/- 9 years), and in 21 healthy subjects (8 men and 13 women; mean age 47 +/- 11 years). In patients with syndrome X the slope of the regression line of heart rate versus time (heart rate/time slope) during exercise testing was similar to that of patients with coronary artery disease (3.3 +/- 0.8 versus 3.1 +/- 1.2 beats/min), but significantly lower than that in healthy subjects (4.2 +/- 1.1 beats/min; p less than 0.003). In patients with syndrome X the intercept of the heart rate/time slope was significantly higher than that in coronary artery disease patients and healthy subjects (102 +/- 15, 86 +/- 18, and 90 +/- 16 beats/min, respectively; p less than 0.015). Resting preexercise heart rate was also significantly higher in syndrome X, compared with coronary artery disease patients and healthy subjects (91 +/- 16, 79 +/- 16, and 80 +/- 14 beats/min, respectively). During ambulatory ECG monitoring, mean diurnal heart rate (from 6 AM to 6 PM) was higher in patients with syndrome X (83 +/- 8 beats/min) than in patients with coronary artery disease (75 +/- 8 beats/min) and healthy subjects (74 +/- 11 beats/min) (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial ischemia caused by distal coronary-artery constriction in stable angina pectoris.

BACKGROUND: In patients with stable coronary artery disease, the ischemic threshold for the production of effort-related angina is often quite variable. Although this feature is commonly attributed to changes in the caliber of coronary arteries at the site of stenosis, it could also be caused by the constriction of distal vessels, collateral vessels, or both. METHODS: In order to test this hypothesis, we studied 11 patients with stable angina, total occlusion of a single coronary artery that was supplied by collateral vessels, normal ventricular function, no evidence of coronary-artery spasm, and no other coronary stenoses. These conditions precluded the modulation of coronary flow by vasomotion at the site of the coronary stenosis. RESULTS: The ischemic threshold--assessed by multiplying the heart rate by the systolic blood pressure at a 1-mm depression of the ST segment during exercise testing--increased by 19 percent after the administration of nitroglycerin (P less than 0.05) and decreased by 18 percent after the administration of ergonovine (P less than 0.01). Ambulatory electrocardiographic monitoring of the patients when not receiving treatment detected 73 ischemic episodes that, in keeping with the history, showed variations of 25 to 52 beats per minute in the heart rate at a 1-mm depression of the ST segment; 12 episodes of sinus tachycardia exceeded the lowest ischemic heart rate by a mean (+/- SD) of 22 +/- 13 beats per minute without ST-segment depression. Furthermore, 21 ischemic episodes occurred at a heart rate more than 25 beats per minute below that at a 1-mm depression of the ST segment during exercise testing. Delayed and reduced filling of collateral and collateralized vessels associated with depression of the ST segment similar to that observed during ambulatory monitoring was detected on angiographic evaluation after the intracoronary administration of ergonovine in three patients. CONCLUSIONS: We propose that the constriction of distal coronary arteries, collateral vessels, or both may cause myocardial ischemia in patients with chronic stable angina.

Recovery-phase patterns of ST segment depression in the heart rate domain cannot distinguish between anginal patients with coronary artery disease and patients with syndrome X.

Continuous plots of ST segment depression related to heart rate during exercise and recovery (heart rate recovery loops) can differentiate patients with coronary artery disease from clinically normal subjects. To assess whether this method can also distinguish patients with angina and coronary artery disease from those with syndrome X (angina, positive exercise tests, and normal coronary arteries), we studied 75 patients with coronary artery disease and 30 patients with syndrome X. The average heart rate recovery loops for coronary artery disease and syndrome X patients followed similar counterclockwise loop rotations. Individual data analysis, however, showed that in coronary artery disease patients the loop rotation was counterclockwise in 66 (88%) and intermediate in nine (12%), while none had a clockwise loop nine (30%), and intermediate in nine (30%). Thus heart rate recovery loops cannot distinguish patients with angina and coronary artery disease from those with syndrome X.